Publications by authors named "Victor J Thannickal"

214 Publications

AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.

Sci Rep 2021 Jun 11;11(1):12387. Epub 2021 Jun 11.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA.

Metabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2 murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.
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http://dx.doi.org/10.1038/s41598-021-90573-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196038PMC
June 2021

Myofibroblast Functions in Tissue Repair and Fibrosis: An Introduction.

Methods Mol Biol 2021 ;2299:9-15

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Our understanding of myofibroblast biology has advanced over the past two decades, and the seemingly antagonistic roles of these cells in both normal tissue repair and fibrotic diseases are better reconciled. An age-related loss of cellular plasticity that results in impaired capacity for de-differentiation and apoptosis susceptibility may predispose individuals to non-resolving and progressive fibrotic disorders involving diverse organ systems.
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http://dx.doi.org/10.1007/978-1-0716-1382-5_2DOI Listing
January 2021

Extracellular Vesicle Mediated Tumor-Stromal Crosstalk Within an Engineered Lung Cancer Model.

Front Oncol 2021 23;11:654922. Epub 2021 Apr 23.

Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.

Tumor-stromal interactions within the tumor microenvironment (TME) influence lung cancer progression and response to therapeutic interventions, yet traditional studies fail to replicate the complexity of these interactions. Herein, we developed three-dimensional (3D) lung tumor models that mimic the human TME and demonstrate tumor-stromal crosstalk mediated by extracellular vesicles (EVs). EVs released by tumor cells, independent of p53 status, and fibroblasts within the TME mediate immunomodulatory effects; specifically, monocyte/macrophage polarization to a tumor-promoting M2 phenotype within this 3D-TME. Additionally, immune checkpoint inhibition in a 3D model that included T cells showed an inhibition of tumor growth and reduced hypoxia within the TME. Thus, perfused 3D tumor models incorporating diverse cell types provide novel insights into EV-mediated tumor-immune interactions and immune-modulation for existing and emerging cancer therapies.
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http://dx.doi.org/10.3389/fonc.2021.654922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103208PMC
April 2021

Divergent Regulation of Alveolar Type 2 Cell and Fibroblast Apoptosis by Plasminogen Activator Inhibitor 1 in Lung Fibrosis.

Am J Pathol 2021 07 20;191(7):1227-1239. Epub 2021 Apr 20.

Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address:

Increased apoptosis sensitivity of alveolar type 2 (ATII) cells and increased apoptosis resistance of (myo)fibroblasts, the apoptosis paradox, contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF). The mechanism underlying the apoptosis paradox in IPF lungs, however, is unclear. Aging is the greatest risk factor for IPF. In this study, we show, for the first time, that ATII cells from old mice are more sensitive, whereas fibroblasts from old mice are more resistant, to apoptotic challenges, compared with the corresponding cells from young mice. The expression of plasminogen activator inhibitor 1 (PAI-1), an important profibrogenic mediator, was significantly increased in both ATII cells and lung fibroblasts from aged mice. In vitro studies using PAI-1 siRNA and active PAI-1 protein indicated that PAI-1 promoted ATII cell apoptosis but protected fibroblasts from apoptosis, likely through dichotomous regulation of p53 expression. Deletion of PAI-1 in adult mice led to a reduction in p53, p21, and Bax protein expression, as well as apoptosis sensitivity in ATII cells, and their increase in the lung fibroblasts, as indicated by in vivo studies. This increase was associated with an attenuation of lung fibrosis after bleomycin challenge. Since PAI-1 is up-regulated in both ATII cells and fibroblasts in IPF, the results suggest that increased PAI-1 may underlie the apoptosis paradox of ATII cells and fibroblasts in IPF lungs.
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http://dx.doi.org/10.1016/j.ajpath.2021.04.003DOI Listing
July 2021

Citrullinated vimentin mediates development and progression of lung fibrosis.

Sci Transl Med 2021 03;13(585)

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induced the secretion of Cit-Vim in an Akt1- and peptidylarginine deiminase 2 (PAD2)-dependent manner. Cit-Vim mediated fibroblast invasion in a 3D ex vivo model of human pulmospheres that resulted in higher expression of CD26, collagen, and α-SMA. Cit-Vim activated NF-κB in a TLR4-dependent fashion and induced the production of active TGF-β1, CTGF, and IL-8 along with higher surface expression of TLR4 in lung fibroblasts. To corroborate ex vivo findings, mice treated with Cit-Vim, but not Vim, independently developed a similar pattern of fibrotic tissue remodeling, which was TLR4 dependent. Moreover, wild-type mice, but not and TLR4 mutant (MUT) mice, exposed to Cd/CB generated high amounts of Cit-Vim, in both plasma and bronchoalveolar lavage fluid, and developed lung fibrosis in a stereotypic manner. Together, these studies support a role for Cit-Vim as a damage-associated molecular pattern molecule (DAMP) that is generated by lung macrophages in response to environmental Cd/CB exposure. Furthermore, PAD2 might represent a promising target to attenuate Cd/CB-induced fibrosis.
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http://dx.doi.org/10.1126/scitranslmed.aba2927DOI Listing
March 2021

Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice.

J Exp Med 2021 May;218(5)

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL.

Aging is a strong risk factor and an independent prognostic factor for progressive human idiopathic pulmonary fibrosis (IPF). Aged mice develop nonresolving pulmonary fibrosis following lung injury. In this study, we found that mouse double minute 4 homolog (MDM4) is highly expressed in the fibrotic lesions of human IPF and experimental pulmonary fibrosis in aged mice. We identified MDM4 as a matrix stiffness-regulated endogenous inhibitor of p53. Reducing matrix stiffness down-regulates MDM4 expression, resulting in p53 activation in primary lung myofibroblasts isolated from IPF patients. Gain of p53 function activates a gene program that sensitizes lung myofibroblasts to apoptosis and promotes the clearance of apoptotic myofibroblasts by macrophages. Destiffening of the fibrotic lung matrix by targeting nonenzymatic cross-linking or genetic ablation of Mdm4 in lung (myo)fibroblasts activates the Mdm4-p53 pathway and promotes lung fibrosis resolution in aged mice. These findings suggest that mechanosensitive MDM4 is a molecular target with promising therapeutic potential against persistent lung fibrosis associated with aging.
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http://dx.doi.org/10.1084/jem.20202033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953267PMC
May 2021

Oxidative cross-linking of fibronectin confers protease resistance and inhibits cellular migration.

Sci Signal 2020 08 11;13(644). Epub 2020 Aug 11.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama, Birmingham, AL 35294, USA.

The oxidation of tyrosine residues to generate '-dityrosine cross-links in extracellular proteins is necessary for the proper function of the extracellular matrix (ECM) in various contexts in invertebrates. Tyrosine oxidation is also required for the biosynthesis of thyroid hormone in vertebrates, and there is evidence for oxidative cross-linking reactions occurring in extracellular proteins secreted by myofibroblasts. The ECM protein fibronectin circulates in the blood as a globular protein that dimerizes through disulfide bridges generated by cysteine oxidation. We found that cellular (fibrillar) fibronectin on the surface of transforming growth factor-β1 (TGF-β1)-activated human myofibroblasts underwent multimerization by -dityrosine cross-linking under reducing conditions that disrupt disulfide bridges, but soluble fibronectin did not. This reaction on tyrosine residues required both the TGF-β1-dependent production of hydrogen peroxide and the presence of myeloperoxidase (MPO) derived from inflammatory cells, which are active participants in wound healing and fibrogenic processes. Oxidative cross-linking of matrix fibronectin attenuated both epithelial and fibroblast migration and conferred resistance to proteolysis by multiple proteases. The abundance of circulating -dityrosine-modified fibronectin was increased in a murine model of lung fibrosis and in human subjects with interstitial lung disease compared to that in control healthy subjects. These studies indicate that tyrosine can undergo stable, covalent linkages in fibrillar fibronectin under inflammatory conditions and that this modification affects the migratory behavior of cells on such modified matrices, suggesting that this modification may play a role in both physiologic and pathophysiologic tissue repair.
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http://dx.doi.org/10.1126/scisignal.aau2803DOI Listing
August 2020

ENERGY SENSING PATHWAYS IN AGING AND CHRONIC LUNG DISEASE.

Trans Am Clin Climatol Assoc 2020 ;131:286-293

BIRMINGHAM, ALABAMA.

Aging is associated with an increased risk of a number of clinical syndromes, including chronic lung disease. There have been significant advances in our understanding of the biology of aging leading to the elucidation of the so-called "hallmarks of aging." The cause-effect relationships between various hallmarks such as dysregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence are not well understood. Here, I discuss the evidence for alterations in energy/metabolic sensing pathways in the degenerative chronic lung disease called idiopathic pulmonary fibrosis (IPF). The pathobiological mechanisms by which this defect may contribute to age-related susceptibility to IPF and potentially other diseases of the elderly are also discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358504PMC
March 2021

Elixir of Youth: Lipid Signaling Chaperones Synthesized in the Liver.

Dev Cell 2020 06;53(6):625-626

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address:

Organ fibrosis represents a default tissue program activated when regenerative capacity is limited. In this issue of Developmental Cell, Ding et al. identify a lipid signaling pathway involving the liver synthesized chaperone ApoM as a circulating pro-regenerative mediator that is deficient in aging and mitigates fibrosis in distant organs.
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http://dx.doi.org/10.1016/j.devcel.2020.06.001DOI Listing
June 2020

ATF4 Mediates Mitochondrial Unfolded Protein Response in Alveolar Epithelial Cells.

Am J Respir Cell Mol Biol 2020 10;63(4):478-489

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.

Although endoplasmic reticulum (ER) unfolded protein response (UPR) is well known, mitochondrial unfolded protein response (UPR) has not been recognized in alveolar epithelial cells. Furthermore, ER stress and mitochondrial dysfunction are frequently encountered in alveolar epithelial cells from an array of lung disorders. However, these two scenarios have been often regarded as separate mechanisms contributing to the pathogeneses. It is unclear whether there is interplay between these two phenomena or an integrator that couples these two signaling cascades in the stressed alveolar epithelial cells from those pathologies. In this study, we defined UPR in alveolar epithelial cells and identified ATF4 (activating transcription factor 4), but not ATF5, as the key regulator of UPR. We found that UPR led to UPR and mitochondrial dysfunction in an ATF4-dependent manner. In contrast, mitochondrial stresses did not activate UPR. We found that alveolar epithelial ATF4 and UPR were induced in aged mice with experimental pulmonary fibrosis as well as in patients with idiopathic pulmonary fibrosis. Finally, we found that the inducible expression of ATF4 in mouse alveolar epithelial cells aggravated pulmonary UPR, lung inflammation, body weight loss, and death upon bleomycin-induced lung injury. In conclusion, ER stress induces ATF4-dependent UPR and mitochondrial dysfunction, indicating a novel mechanism by which ER stress contributes to the pathogeneses of a variety of pulmonary disorders.
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http://dx.doi.org/10.1165/rcmb.2020-0107OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528926PMC
October 2020

Brd4-p300 inhibition downregulates Nox4 and accelerates lung fibrosis resolution in aged mice.

JCI Insight 2020 07 23;5(14). Epub 2020 Jul 23.

Tissue regeneration capacity declines with aging in association with heightened oxidative stress. Expression of the oxidant-generating enzyme, NADPH oxidase 4 (Nox4), is elevated in aged mice with diminished capacity for fibrosis resolution. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal (BET) family of proteins that function as epigenetic "readers" of acetylated lysine groups on histones. In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. BET inhibition interferes with the association of Brd4, p300, and acetylated histone H4K16 with the Nox4 promoter in lung fibroblasts stimulated with the profibrotic cytokine, TGF-β1. A number of BET inhibitors, including I-BET-762, JQ1, and OTX015, downregulate Nox4 gene expression and activity. Aged mice with established and persistent lung fibrosis recover capacity for fibrosis resolution with OTX015 treatment. This study implicates epigenetic regulation of Nox4 by Brd4 and p300 and supports BET/Brd4 inhibition as an effective strategy for the treatment of age-related fibrotic lung disease.
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http://dx.doi.org/10.1172/jci.insight.137127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453889PMC
July 2020

Airway Remodeling in Asthma.

Front Med (Lausanne) 2020 21;7:191. Epub 2020 May 21.

Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.

Asthma is an inflammatory disease of the airways that may result from exposure to allergens or other environmental irritants, resulting in bronchoconstriction, wheezing, and shortness of breath. The structural changes of the airways associated with asthma, broadly referred to as airway remodeling, is a pathological feature of chronic asthma that contributes to the clinical manifestations of the disease. Airway remodeling in asthma constitutes cellular and extracellular matrix changes in the large and small airways, epithelial cell apoptosis, airway smooth muscle cell proliferation, and fibroblast activation. These pathological changes in the airway are orchestrated by crosstalk of different cell types within the airway wall and submucosa. Environmental exposures to dust, chemicals, and cigarette smoke can initiate the cascade of pro-inflammatory responses that trigger airway remodeling through paracrine signaling and mechanostimulatory cues that drive airway remodeling. In this review, we explore three integrated and dynamic processes in airway remodeling: (1) initiation by epithelial cells; (2) amplification by immune cells; and (3) mesenchymal effector functions. Furthermore, we explore the role of inflammaging in the dysregulated and persistent inflammatory response that perpetuates airway remodeling in elderly asthmatics.
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http://dx.doi.org/10.3389/fmed.2020.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253669PMC
May 2020

Redox biology and therapeutics in chronic lung disease.

Redox Biol 2020 06 11;33:101579. Epub 2020 May 11.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, 1900 University Blvd, THT 541E, Birmingham, AL, 35294, USA. Electronic address:

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http://dx.doi.org/10.1016/j.redox.2020.101579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251235PMC
June 2020

Heme metabolism genes Downregulated in COPD Cachexia.

Respir Res 2020 May 1;21(1):100. Epub 2020 May 1.

Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.

Introduction: Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.

Methods: We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m among women and < 17 kg/m among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.

Results: The prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).

Discussion: Several replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage.
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http://dx.doi.org/10.1186/s12931-020-01336-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193359PMC
May 2020

The natural history of progressive fibrosing interstitial lung diseases.

Eur Respir J 2020 06 25;55(6). Epub 2020 Jun 25.

National Heart and Lung Institute, Imperial College, London, UK.

We used data from the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing interstitial lung diseases (ILDs).Subjects in the two INPULSIS trials had a clinical diagnosis of idiopathic pulmonary fibrosis (IPF) while subjects in the INBUILD trial had a progressive fibrosing ILD other than IPF and met protocol-defined criteria for ILD progression despite management. Using data from the placebo groups, we compared the rate of decline in forced vital capacity (FVC) (mL·year) and mortality over 52 weeks in the INBUILD trial with pooled data from the INPULSIS trials.The adjusted mean annual rate of decline in FVC in the INBUILD trial (n=331) was similar to that observed in the INPULSIS trials (n=423) (-192.9 mL·year and -221.0 mL·year, respectively; nominal p-value=0.19). The proportion of subjects who had a relative decline in FVC >10% predicted at Week 52 was 48.9% in the INBUILD trial and 48.7% in the INPULSIS trials, and the proportion who died over 52 weeks was 5.1% in the INBUILD trial and 7.8% in the INPULSIS trials. A relative decline in FVC >10% predicted was associated with an increased risk of death in the INBUILD trial (hazard ratio 3.64) and the INPULSIS trials (hazard ratio 3.95).These findings indicate that patients with fibrosing ILDs other than IPF, who are progressing despite management, have a subsequent clinical course similar to patients with untreated IPF, with a high risk of further ILD progression and early mortality.
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http://dx.doi.org/10.1183/13993003.00085-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315005PMC
June 2020

Oxidative Stress in Pulmonary Fibrosis.

Compr Physiol 2020 03 12;10(2):509-547. Epub 2020 Mar 12.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Oxidative stress has been linked to various disease states as well as physiological aging. The lungs are uniquely exposed to a highly oxidizing environment and have evolved several mechanisms to attenuate oxidative stress. Idiopathic pulmonary fibrosis (IPF) is a progressive age-related disorder that leads to architectural remodeling, impaired gas exchange, respiratory failure, and death. In this article, we discuss cellular sources of oxidant production, and antioxidant defenses, both enzymatic and nonenzymatic. We outline the current understanding of the pathogenesis of IPF and how oxidative stress contributes to fibrosis. Further, we link oxidative stress to the biology of aging that involves DNA damage responses, loss of proteostasis, and mitochondrial dysfunction. We discuss the recent findings on the role of reactive oxygen species (ROS) in specific fibrotic processes such as macrophage polarization and immunosenescence, alveolar epithelial cell apoptosis and senescence, myofibroblast differentiation and senescence, and alterations in the acellular extracellular matrix. Finally, we provide an overview of the current preclinical studies and clinical trials targeting oxidative stress in fibrosis and potential new strategies for future therapeutic interventions. © 2020 American Physiological Society. Compr Physiol 10:509-547, 2020.
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http://dx.doi.org/10.1002/cphy.c190017DOI Listing
March 2020

NADPH Oxidase Inhibition in Fibrotic Pathologies.

Antioxid Redox Signal 2020 08 4;33(6):455-479. Epub 2020 Mar 4.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Fibrosis is a stereotypic, multicellular tissue response to diverse types of injuries that fundamentally result from a failure of cell/tissue regeneration. This complex tissue remodeling response disrupts cellular/matrix composition and homeostatic cell-cell interactions, leading to loss of normal tissue architecture and progressive loss of organ structure/function. Fibrosis is a common feature of chronic diseases that may affect the lung, kidney, liver, and heart. There is emerging evidence to support a combination of genetic, environmental, and age-related risk factors contributing to susceptibility and/or progression of fibrosis in different organ systems. A core pathway in fibrogenesis involving these organs is the induction and activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX) family enzymes. We explore current pharmaceutical approaches to targeting NOX enzymes, including repurposing of currently U.S. Food and Drug Administration (FDA)-approved drugs. Specific inhibitors of various NOX homologs will aid establishing roles of NOXs in the various organ fibroses and potential efficacy to impede/halt disease progression. The discovery of novel and highly specific NOX inhibitors will provide opportunities to develop NOX inhibitors for treatment of fibrotic pathologies.
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http://dx.doi.org/10.1089/ars.2020.8032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370982PMC
August 2020

Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging.

Am J Respir Cell Mol Biol 2020 05;62(5):633-644

Division of Pulmonary, Allergy and Critical Care and Sleep Medicine, University of Arizona, Tucson, Arizona.

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease with no cure. Although IPF is widely regarded as a disease of aging, the cellular mechanisms that contribute to this age-associated predilection remain elusive. In this study, we sought to evaluate the consequences of senescence on myofibroblast cell fate and fibrotic responses to lung injury in the context of aging. We demonstrated that nonsenescent lung myofibroblasts maintained the capacity for dedifferentiation, whereas senescent/IPF myofibroblasts exhibited an impaired capacity for dedifferentiation. We previously demonstrated that the transcription factor MyoD acts as a critical switch in the differentiation and dedifferentiation of myofibroblasts. Here, we demonstrate that decreased levels of MyoD preceded myofibroblast dedifferentiation and apoptosis susceptibility in nonsenescent cells, whereas MyoD expression remained elevated in senescent/IPF myofibroblasts, which failed to undergo dedifferentiation and demonstrated resistance to apoptosis. Genetic strategies to silence MyoD restored the susceptibility of IPF myofibroblasts to undergo apoptosis and led to a partial reversal of age-associated persistent fibrosis . The capacity for myofibroblast dedifferentiation and subsequent apoptosis may be critical for normal physiologic responses to tissue injury, whereas restricted dedifferentiation and apoptosis resistance in senescent cells may underlie the progressive nature of age-associated human fibrotic disorders. These studies support the concept that senescence may promote profibrotic effects via impaired myofibroblast dedifferentiation and apoptosis resistance, which contributes to myofibroblast accumulation and ultimately persistent fibrosis in aging.
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http://dx.doi.org/10.1165/rcmb.2019-0092OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193787PMC
May 2020

The senescence-associated matricellular protein CCN1 in plasma of human subjects with idiopathic pulmonary fibrosis.

Respir Med 2020 01 19;161:105821. Epub 2019 Nov 19.

Division of Pulmonary, Allergy, Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Introduction: Cellular senescence has been linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF). CCN1 is a matricellular protein that has been shown to induce cellular senescence and contribute to lung fibrosis in pre-clinical models. In this report, we determined plasma CCN1 levels in patients with IPF and its potential role in clinical outcomes.

Methods And Results: We evaluated 88 patients diagnosed with IPF at the University of Alabama at Birmingham. CCN1 levels were measured in plasma specimens by ELISA. The primary outcome measure was transplant-free survival (TFS) duration. High-CCN1 levels were associated with a lower transplant-free survival independent of %FVC and %DCO compared to patients with low plasma CCN1 (HR = 2.15; 95%CI 1.04-4.45, p = 0.04).

Conclusion: This study demonstrates that plasma levels of CCN1 may be predictive of survival in IPF. Given the plausible role of CCN1 in cellular senescence and pathobiology of IPF, the predictive value of CCN1 in disease progression among patients with IPF warrants further investigation.
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http://dx.doi.org/10.1016/j.rmed.2019.105821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023981PMC
January 2020

PAI-1 Regulation of TGF-β1-induced Alveolar Type II Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages.

Am J Respir Cell Mol Biol 2020 03;62(3):319-330

Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.

Senescence of alveolar type II (ATII) cells, progenitors of the alveolar epithelium, is a pathological feature and contributes importantly to the pathogenesis of idiopathic pulmonary fibrosis. Despite recognition of the importance of ATII cell senescence in idiopathic pulmonary fibrosis pathogenesis, how ATII cell senescence is regulated and how senescent ATII cells contribute to lung fibrogenesis remain unclear. In this study, we show that TGF-β1 (transforming growth factor-β1), a most ubiquitous and potent profibrotic cytokine, induces plasminogen activator inhibitor-1 (PAI-1), a cell senescence and fibrosis mediator, and p16 as well as senescence, but not apoptosis, in primary mouse ATII cells. We also found that senescent ATII cells secrete various cytokines and chemokines, including IL-4 and IL-13, which stimulate the expression of genes associated with a profibrotic phenotype in alveolar macrophages. Similar responses were also observed in TGF-β1-treated rat ATII (L2) and rat macrophage NR8383 cells. Deletion of PAI-1 or inhibition of PAI-1 activity with a small molecule PAI-1 inhibitor, however, blocks TGF-β1-induced senescence as well as a senescence-associated secretory phenotype in ATII and L2 cells and, consequently, the stimulatory effects of the conditioned medium from senescent ATII/L2 cells on macrophages. Moreover, we show that silencing p16 ameliorates PAI-1 protein-induced ATII cell senescence and secretion of profibrotic mediators. Our data suggest that PAI-1 mediates TGF-β1-induced ATII cell senescence and secretion of profibrotic mediators through inducing p16, and they also suggest that senescent ATII cells contribute to lung fibrogenesis in part by activating alveolar macrophages through secreting profibrotic and proinflammatory mediators.
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http://dx.doi.org/10.1165/rcmb.2019-0071OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055702PMC
March 2020

NOX4 modulates macrophage phenotype and mitochondrial biogenesis in asbestosis.

JCI Insight 2019 08 22;4(16). Epub 2019 Aug 22.

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, and.

Macrophage activation is implicated in the development of pulmonary fibrosis by generation of profibrotic molecules. Although NADPH oxidase 4 (NOX4) is known to contribute to pulmonary fibrosis, its effects on macrophage activation and mitochondrial redox signaling are unclear. Here, we show that NOX4 is crucial for lung macrophage profibrotic polarization and fibrotic repair after asbestos exposure. NOX4 was elevated in lung macrophages from subjects with asbestosis, and mice harboring a deletion of NOX4 in lung macrophages were protected from asbestos-induced fibrosis. NOX4 promoted lung macrophage profibrotic polarization and increased production of profibrotic molecules that induce collagen deposition. Mechanistically, NOX4 further augmented mitochondrial ROS production and induced mitochondrial biogenesis. Targeting redox signaling and mitochondrial biogenesis prevented the profibrotic polarization of lung macrophages by reducing the production of profibrotic molecules. These observations provide evidence that macrophage NOX4 is a potentially novel therapeutic target to halt the development of asbestos-induced pulmonary fibrosis.
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http://dx.doi.org/10.1172/jci.insight.126551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777818PMC
August 2019

Identification of an emphysema-associated genetic variant near with regulatory effects in lung fibroblasts.

Elife 2019 07 25;8. Epub 2019 Jul 25.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States.

Murine studies have linked TGF-β signaling to emphysema, and human genome-wide association studies (GWAS) studies of lung function and COPD have identified associated regions near genes in the TGF-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying 10 GWAS loci including an association peak spanning a 200 kb region downstream from . Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a ~ 100 bp region containing rs1690789 resulted in decreased expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-β pathway to emphysema in humans.
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http://dx.doi.org/10.7554/eLife.42720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693893PMC
July 2019

Remember Me? The Bone Marrow in Pulmonary Fibrosis.

Am J Respir Crit Care Med 2019 10;200(8):959-960

Division of Pulmonary, Allergy and Critical Care MedicineUniversity of Alabama at BirminghamBirmingham, Alabama.

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http://dx.doi.org/10.1164/rccm.201906-1101EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794115PMC
October 2019

NADPH Oxidases and Aging Models of Lung Fibrosis.

Methods Mol Biol 2019 ;1982:487-496

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

There is a growing recognition that aging is a risk factor for fibrosis that affects a number of organ systems, including the lung. Despite this understanding, most studies of experimental fibrosis have been conducted in young mice that typically resolve injury-induced lung fibrosis over the course of several months. Our studies demonstrate that aged mouse models may recapitulate human disease by generating a more persistent fibrotic response to injury. This is, in part, due to an imbalance in the expression and activity of NADPH oxidase (NOX) enzymes, in particular the NOX4 isoform, and a related deficiency in antioxidant responses in pathogenic myofibroblasts. These pathogenic myofibroblasts acquire features of cellular senescence and become resistant to apoptosis. In this chapter, we present methods and procedures to apply the aging model of lung fibrosis in mice that will allow interrogation of myofibroblast functions and the expression and activity of NOX4 in cells. We provide recommendations for best laboratory practices to assess the severity and resolution of fibrosis in murine models of aging.
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http://dx.doi.org/10.1007/978-1-4939-9424-3_29DOI Listing
January 2020

Modeling Fibrosis in Three-Dimensional Organoids Reveals New Epithelial Restraints on Fibroblasts.

Am J Respir Cell Mol Biol 2019 11;61(5):556-557

Department of MedicineUniversity of Alabama at BirminghamBirmingham, Alabama.

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http://dx.doi.org/10.1165/rcmb.2019-0153EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827065PMC
November 2019

FGF10-FGFR2B Signaling Generates Basal Cells and Drives Alveolar Epithelial Regeneration by Bronchial Epithelial Stem Cells after Lung Injury.

Stem Cell Reports 2019 05 2;12(5):1041-1055. Epub 2019 May 2.

Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, THT 422, 1720 2nd Avenue S., Birmingham, 35294-2182 AL, USA. Electronic address:

Idiopathic pulmonary fibrosis is a common form of interstitial lung disease resulting in alveolar remodeling and progressive loss of pulmonary function because of chronic alveolar injury and failure to regenerate the respiratory epithelium. Histologically, fibrotic lesions and honeycomb structures expressing atypical proximal airway epithelial markers replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Bronchial epithelial stem cells (BESCs) can give rise to AT2 and AT1 cells or honeycomb cysts following bleomycin-mediated lung injury. However, little is known about what controls this binary decision or whether this decision can be reversed. Here we report that inactivation of Fgfr2b in BESCs impairs their contribution to both alveolar epithelial regeneration and honeycomb cysts after bleomycin injury. By contrast overexpression of Fgf10 in BESCs enhances fibrosis resolution by favoring the more desirable outcome of alveolar epithelial regeneration over the development of pathologic honeycomb cysts.
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http://dx.doi.org/10.1016/j.stemcr.2019.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524168PMC
May 2019

Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis.

Am J Physiol Lung Cell Mol Physiol 2019 07 1;317(1):L141-L154. Epub 2019 May 1.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama , Birmingham, Alabama.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an "age-suppressing" hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.
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http://dx.doi.org/10.1152/ajplung.00246.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689746PMC
July 2019

Update in Pulmonary Fibrosis 2018.

Am J Respir Crit Care Med 2019 08;200(3):292-300

1Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1164/rccm.201903-0542UPDOI Listing
August 2019

The Aging Lung and Idiopathic Pulmonary Fibrosis.

Am J Med Sci 2019 05 12;357(5):384-389. Epub 2019 Feb 12.

Division of Pulmonary, Allergy, and Critical Care Medicine and; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Idiopathic pulmonary fibrosis (IPF) is one of many clinical syndromes that are associated with aging, and is increasing in both incidence and prevalence with the rapid rise in aging populations world-wide. There is accumulating data on how the biology of aging may influence the susceptibility to lung fibrosis in the elderly. In this review, we explore some of the known "hallmarks of aging," including telomere attrition, genomic instability, epigenetic alterations, loss of proteostasis, cellular senescence and mitochondrial dysfunction in the pathobiology of IPF. Additionally, we discuss age-associated alterations in extracellular matrix that may contribute to the development and/or progression of IPF.
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http://dx.doi.org/10.1016/j.amjms.2019.02.008DOI Listing
May 2019
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